Peripheral arterial disease (PAD) of the lower extremities affects more than 5 million adults in the US and remains unresolved by intervention. Bare metal stents deployed in peripheral arteries fail because they lack anti-proliferative drugs and fracture at high rates (up to 68%) due to severe peripheral artery deformation (twisting, bending, and shortening). Drug eluting stents (DES) fail as their anti-proliferative drugs are not delivered to or retained by the medial wall. DES are also limited to vessel size, which precludes their use in below-the-knee (BTK) applications where vessel diameters are less than 2.0 mm. Treatment of BTK vessels are essential for limb salvage in diabetic patients with PAD, however in these circumstances, balloon angioplasty is the only option. Unfortunately, restenosis rates of balloon angioplasty are higher compare to stents. The proposed study will develop a new strategy to deliver and retain anti-proliferative drugs without the use of a metallic platform as a means of treating PAD. This will be accomplished using a state-of-the-art balloon perfusion catheter and a drug carrier keratin, a protein extracted from human hair. Keratin provides a mean to deliver the anti-proliferative agent paclitaxel at a controlled rate and increase retention in the vessel wall. In addition, keratin elicits beneficial inflammatory responses during early phase of healing. It is hypothesized that a paclitaxel-keratin excipient delivered at a controlled rate by the perfusion catheter to the lesion wall results in medial smooth muscle cell quiescence and rapid re-endothelialization. Varying keratin concentration and loading parameters will first be tested to optimize paclitaxel delivery and retention using the perfusion catheter (Specific Aim 1). These studies will be accomplished using a novel ex vivo porcine artery circulatory system that accurately predicts drug retention and saves resources and animal utilization. In addition, the vascular response to the keratin-paclitaxel will be evaluated in a relevant pre-clinical model (Specific Aim 2). Specifically, paclitaxel arterial levels will be measured by pharmacokinetic analysis up to 28 days. Smooth muscle cell proliferation, vessel remodeling, injury and inflammation will be quantified by histopathology. Endothelial cell recovery will be quantified by scanning electron microscopy and fluorescent microscopy. Through these aims, we will demonstrate the effectiveness of the perfusion catheter to deliver paclitaxel-keratin excipient and to inhibit neointimal growth, reduce inflammatory infiltrates and improve re- endothelialization. Ultimately, this approach can overcome limitations of current interventional devices and improve the quality of life for millions of patients suffering with PAD.